Projects per year
Abstract
Grb7 is an adapter protein, overexpressed in HER2+ve breast and other cancers, and identified as a therapeutic target. Grb7 promotes both proliferative and migratory cellular pathways through interaction of its SH2 domain with upstream binding partners including HER2, SHC, and FAK. Here we present the evaluation of a series of monocyclic and bicyclic peptide inhibitors that have been developed to specifically and potently target the Grb7 SH2-domain. All peptides tested were found to inhibit signaling in both ERK and AKT pathways in SKBR-3 and MDA-MB-231 cell lines. Proliferation, migration, and invasion assays revealed, however, that the second-generation bicyclic peptides were not more bioactive than the first generation G7-18NATE peptide, despite their higher in vitro affinity for the target. This was found not to be due to steric hindrance by the cell-permeability tag, as ascertained by ITC, but to differences in the ability of the bicyclic peptides to interact with and penetrate cellular membranes, as determined using SPR and mass spectrometry. These studies reveal that just small differences to amino acid composition can greatly impact the effectiveness of peptide inhibitors to their intracellular target and demonstrate that G7-18NATE remains the most effective peptide inhibitor of Grb7 developed to date.
Original language | English |
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Article number | 3739 |
Number of pages | 19 |
Journal | Molecules |
Volume | 24 |
Issue number | 20 |
DOIs | |
Publication status | Published - 17 Oct 2019 |
Keywords
- Bicyclic peptide
- Cancer cell migration
- Cell penetrating peptide
- Grb7
- Inhibitor binding
- Invasion
- Lipid bilayer interactions
- Mass spectrometry quantification
- Proliferation
- SH2-domain
Projects
- 1 Finished
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Design and delivery of peptide-based anti-cancer Grb7 inhibitors
Wilce, J., Perlmutter, P. & Pero, S.
National Health and Medical Research Council (NHMRC) (Australia)
1/01/13 → 30/06/16
Project: Research